Medical Device Daily Washington Editor
WASHINGTON — The meeting of the FDA’s circulatory systems device panel today and tomorrow in Gaithersburg, Maryland, is looking at a number of increasingly vexing questions about drug-eluting stent (DES) technology. But during a Tuesday conference call hosted by the agency, Daniel Schultz, the director of the Center for Devices and Radiological Health , gave no indication whether the center is leaning toward changing its policies concerning how it regulates this now-controversial class of products.
However, at least one company in this sector, Medtronic (Minneapolis), is preparing for the possibility that stent trials will have to run longer and/or enroll more subjects in order to pass regulatory muster.
Among the questions that the agency will seek responses to is whether DES is associated with higher all-cause mortality than bare-metal stent (BMS) devices and whether the safety concerns connected to DES outweigh the benefits compared to use of their BMS plain-Jane cousins. Considerable comment — and perhaps some criticism — of the trials looking at first-generation DES products from Cordis (Miami Lakes, Florida) and Boston Scientific (Natick, Massachusetts) is likely.
A recent meta-analysis of studies indicated that “drug-eluting stents increase the risk for late thrombosis 4- to 5-fold compared” to BMS but that the overall rate of thrombosis from all the studies in the review was fairly similar between DES and BMS. The article describing the meta-analysis, in the December edition of the American Journal of Medicine, stated that the rate of thrombosis “was 9.3 events per 1,000 drug-eluting stent patients compared with 9.0 events per 1,000” patients BMS-implanted.
Schultz said in the Dec. 5 conference call that the agency’s goal “in this meeting is to look at a complex set of issues [that will help] balance risks and benefits” for DES. He added that the panelists will give “the necessary expertise and breadth of view ... that will give us a balanced overview.”
The CDRH chief observed that it is not unusual for the agency to deal with various grey areas of safety in its risk/benefit analyses, but that the agency sees signals in “small numbers” that may point to bigger problems for the DES category. He said that the FDA hopes that this meeting will “provide a template of how we will deal with these issues in the future.”
“One of the most difficult aspects of analyzing and making sense of all the studies was that everyone was using different definitions,” Schultz said, adding that getting agreement to several key definitions is essential. He said that only limited progress will be made until the participants agree on a “common language [so as] to have a discussion that’s productive.”
Another problem with studies done to date is that they did not recruit identical populations. For the FDA, he said these situations make it difficult to “sort through that noise.”
“We would like to see everyone move toward a common definition of performance properties for stents ... but we cannot mandate that,” the FDAer pointed out.
Schultz said that the meeting will include discussions of off-label use as well, but he cautioned that “[w]e need to be careful in how we talk about what goes on between patient and doctor” because they each must be able to make decisions based on the benefit of a therapy to the patient.
Some in industry have suggested that because of the questions raised about previous trials — especially their length — the FDA will consider the idea of requiring longer and/or larger trials for some of these devices combined with pharmaceutical action. The focus thus far has been on DES, but an increasing number of products are using the device/drug combo strategy.
Campbell Rogers, MD, chief technical officer at Cordis, told Medical Device Daily at the Transcatheter Cardiovascular Therapeutics conference in October that that the problems encountered by coated stents have prompted his company to take another look at its clinical trial protocols.
“We’re extending our three open randomized trials from five to eight years,” Rogers said. He said that it is difficult to anticipate how extended trials might affect device development efforts, but that different devices give off “different safety signals” and that this fact may “impact what regulatory agencies ask for” in terms of trial design and safety/efficacy data.
Schultz declined to address this idea directly, saying, “I think that what we would like to do now is understand what information is missing and what we need to collect, and then how to best” optimize clinical studies.
Scott Papillon, a senior public relations manager for Medtronic, told MDD that the firm “submitted the PMA a few weeks ago” for its own offering in the DES category — the Endeavor — but he said he sees no current move by the agency to require more exhaustive trials. Papillon suggested, however, that the data for the Endeavor are likely to meet tougher standards. The trials involved 4,000 subjects followed for two to three years, hence much more thorough than the initial trials for the Cypher and the Taxus.
Papillon also noted that despite what Schultz said about definitions, those used by the three major stent manufacturers in the U.S. “are almost exactly the same.” But he acknowledged that the definition presented recently by the Academic Research Consortium (ARC; Santa Barbara, California) “broadened the word to capture some events,” those events including deaths of patients from circumstances unrelated to their cardiac health status.